CN111067897A - Antifungal composition and application thereof - Google Patents
Antifungal composition and application thereof Download PDFInfo
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- CN111067897A CN111067897A CN202010067033.3A CN202010067033A CN111067897A CN 111067897 A CN111067897 A CN 111067897A CN 202010067033 A CN202010067033 A CN 202010067033A CN 111067897 A CN111067897 A CN 111067897A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
Abstract
The present invention relates to an antifungal composition comprising: a) terbinafine or a pharmaceutically acceptable salt thereof; b) berberine or a pharmaceutically acceptable salt thereof; and c) urea and its use. The present invention also relates to the use of a pharmaceutical composition for the preparation of a medicament for the treatment of fungal infection diseases, said pharmaceutical composition comprising: terbinafine or a pharmaceutically acceptable salt thereof, and berberine or a pharmaceutically acceptable salt thereof; wherein the fungus is selected from the group consisting of trichophyton, fusarium, candida and combinations thereof. The composition of the invention can enhance the sterilization effect, reduce the dosage of the medicine, shorten the treatment course or avoid the drug resistance of the medicine.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a synergistic antifungal composition and application thereof, and also relates to application of a pharmaceutical composition in preparation of medicines for treating fungal infection diseases.
Background
Fungal infectious diseases, i.e. diseases caused by fungi. Fungi, a group of eukaryotes widely existing in nature, infect various parts of the human body. From the clinical pathogenic point of view, mycosis can be divided into superficial mycosis and deep mycosis. The normal flora symbiosis relationship between bacteria and fungi is damaged to a certain extent due to various problems such as antibiotic abuse and the like; secondly, organ transplantation operations are also increasingly clinically applied, and the use of immunosuppressive agents in the operations influences the normal immune function of an organism, so that the resistance of a human body to fungi is reduced, and the incidence rate of fungal infection of deep organs is higher and more serious. Onychomycosis is a chronic nail disease with fungal infection. Treatment of the nail plate is somewhat challenging due to its high degree of hyperkeratosis. The infection sources of fungal nail infections are mainly caused by dermatophytes and non-dermatophytes, including dermatophytes of the genus trichophyton and non-dermatophytes of the genus fusarium, aspergillus fumigatus and candida. The diseases caused by the fungal infection are universal, infectious, recurrent and intractable, and have great harm to the health of human nails. At present, the oral terbinafine or itraconazole is generally used for treatment after the diagnosis is clinically confirmed.
Berberine is one of the main active ingredients of the traditional Chinese medicine coptis chinensis which is commonly used clinically, scholars report that crude berberine has the function of resisting dermatophytes, and related articles also show that the berberine also has good effect on resisting bacterial and fungal biofilm infection. Terbinafine is an allylamine drug, has a relatively obvious antibacterial effect on dermatophytes (such as trichophyton rubrum, microsporum canis and the like), but has a poor antibacterial effect on non-dermatophytes (such as aspergillus fumigatus, fusarium and candida albicans). Terbinafine is the first choice for current anti-nail and skin fungus treatment by inhibiting fungal enzyme squalene epoxidase, thereby inhibiting ergosterol biosynthesis (an important component of fungal cell membrane), and causing toxic squalene to accumulate in fungal cell wall, thereby causing fungal cell death. The terbinafine is available in the form of tablet, spray, cream, solution, gel, liniment, etc., and can be used for treating tinea manuum, tinea pedis, tinea corporis, tinea cruris, tinea versicolor, and cutaneous candidiasis. But it is poorly permeable and has poor therapeutic effects on fungal infections of the nail and deeper parts of the skin. Meanwhile, terbinafine oral preparations usually have adverse reactions such as systemic toxicity, liver toxicity, gastrointestinal irritation and the like, while common semisolid such as cream contains greasy substrates, is difficult to spread when being smeared on affected parts, and is easy to wipe off by clothes after administration, so that greasy feeling and uncomfortable feeling appear on nails or surfaces; the gel is not water-resistant and can be easily washed off during washing hands or bathing. These dosage forms are less patient compliant for the reasons mentioned above.
Therefore, new antifungal drugs are needed to meet the current clinical needs.
Disclosure of Invention
The inventor finds that the combination of terbinafine and berberine can increase antifungal activity, realize synergistic effect, improve antibacterial spectrum of terbinafine, or avoid drug resistance. Meanwhile, after the medicaments are combined and prepared into a film coating agent, the transpirion and the retention of terbinafine hydrochloride through nails can be effectively improved, and the onychomycosis can be effectively treated.
The present invention provides an antifungal composition comprising: a) terbinafine or a pharmaceutically acceptable salt thereof; b) berberine or a pharmaceutically acceptable salt thereof; and c) urea.
In some embodiments, wherein the ratio of terbinafine, or a pharmaceutically acceptable salt thereof: berberine or a pharmaceutically acceptable salt thereof: the mass ratio of urea is as follows: 5-0.5: 10-30. In some embodiments, terbinafine, or a pharmaceutically acceptable salt thereof: berberine or a pharmaceutically acceptable salt thereof: the mass ratio of the urea is 1-0.5: 15-25. In some embodiments, terbinafine, or a pharmaceutically acceptable salt thereof: berberine or a pharmaceutically acceptable salt thereof: the mass ratio of urea is more preferably 1:1: 20.
In some embodiments, wherein the composition further comprises a film forming material, and the composition is a film coating, wherein the film forming material is preferably polyvinyl alcohol, polyvinylpyrrolidone, carbomer, chitosan or Eudragit RLPO. In some embodiments, the pharmaceutically acceptable salt of terbinafine is the hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt of berberine is a hydrochloride salt. In some embodiments, the composition further comprises water, preferably the wt% of water is less than 25%, more preferably the wt% of water is 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or 21%.
In another aspect, the present invention provides the use of any one of the above compositions in the manufacture of a medicament for the treatment of a fungal infection disease, wherein the fungus is selected from trichophyton, fusarium, candida or a combination thereof. In some embodiments, the fungus is selected from trichophyton rubrum, fusarium, candida albicans, or a combination thereof. In some embodiments, the fungal infection disease is onychomycosis.
In a further aspect, the present invention provides the use of a pharmaceutical composition for the manufacture of a medicament for the treatment of fungal infection diseases, said pharmaceutical composition comprising: terbinafine or a pharmaceutically acceptable salt thereof, and berberine or a pharmaceutically acceptable salt thereof; wherein the fungus is selected from the group consisting of trichophyton, fusarium, candida, or combinations thereof. In some embodiments, wherein the fungus is selected from trichophyton rubrum, fusarium, candida albicans, or a combination thereof. In some embodiments, the fungal infection disease is onychomycosis. In some embodiments, the pharmaceutically acceptable salt of terbinafine is the hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt of berberine is a hydrochloride salt.
In some embodiments, wherein the ratio of terbinafine, or a pharmaceutically acceptable salt thereof: the mass ratio of the berberine or the pharmaceutically acceptable salt thereof is as follows: 5-0.5: 5-0.5. In some embodiments, terbinafine, or a pharmaceutically acceptable salt thereof: berberine or a pharmaceutically acceptable salt thereof: the mass ratio of the urea is 1-0.5: 1-0.5. In some embodiments, terbinafine, or a pharmaceutically acceptable salt thereof: the mass ratio of berberine or a pharmaceutically acceptable salt thereof is further preferably 1: 1.
Drawings
FIG. 1A film-forming test study of the combination composition of the present invention (comprising urea), the single pharmaceutical composition (not comprising urea) and the commercial formulation (Lamisil Pedisan once) was conducted. Drying time (A) and film-forming appearance score (B) ((A))P< 0.05, indicates a statistical difference).
Detailed Description
Fungal infectious diseases
A "fungal infectious disease" is any condition or disease caused by a fungus. Fungal infectious diseases can be broadly classified into invasive mycoses, systemic mycoses (such as aspergillosis and candidiasis), mucosal mycoses (such as thrush), superficial dermatomycoses and allergic mycoses (such as asthma and chronic inflammation). The compositions of the present invention are preferably due to superficial mycoses (e.g., tinea capitis, tinea corporis, tinea versicolor, vaginitis, and onychomycosis).
The term "trichophyton" (academic name:Trichophyton) Is a fungus under the phylum Ascomycota. Trichophyton attacks the skin, hair follicles and nails of humans causing skin infections. The genus Trichophyton includes: trichophyton angustifoliumTrichophyton ajelloi、Trichophyton imbricatumTrichophyton concentricum、Trichophyton equiTrichophyton equinum、 Trichophyton flavescens、Trichophyton gloriae、Trichophyton metronatum (Fr.) KuntzeTrichophyton megnini、Trichophyton mentagrophytesTrichophyton mentagrophytes var. erinacei、Trichophyton mentagrophytesTrichophyton mentagrophytes var. interdigitale、Trichophyton phaseoliforme、Trichophyton rubrumTrichophyton rubrum、Trichophyton schoenlandiTrichophyton schoenleinii、Trichophyton monkeyTrichophyton simii、Trichophyton sudanenseTrichophyton soudanense、Trichophyton oxytropisTrichophyton terrestre、Trichophyton trichomonadTrichophyton tonsurans、Trichophyton vanbreuseghemii、Trichophyton verruciformis (Fr.) persTrichophyton verrucosum、Trichophyton purpurea (Fr.) SingTrichophyton violaceum、Trichophyton rubrumTrichophyton yaoundei。The composition of the present invention can treat trichophyton preferably trichophyton rubrum.
The term "Fusarium" includes, for example, Fusarium clavatum, Fusarium cerealis, Fusarium crooki, Fusarium flavum, Fusarium graminearum, Fusarium graminum, Fusarium heterosporum, Fusarium albizium, Fusarium oxysporum, Fusarium reticulatum, Fusarium roseum, Fusarium sambucinum, Fusarium sarcochroum, Fusarium thiochroum, Fusarium torulosum, or Fusarium sporotrichioides. Preferably fusarium is treated in the compositions of the invention.
The term "Candida (Candida) "includes, for example, Candida SchiffCandida ciferrii) Candida innominate (Candidafamata) Candida lamblia (Langerbike: (C.lanigera)Candida lambica) Candida lipolytica (A)Candidalipolytica) Candida Norwegiae (C.), (Candida norvegensis) Candida rugosa (C.rugosa) ((C.rugosa))Candidarugosa) Candida velvetica: (Candida viswanathii) Candida salivarius (C.salivarius)Candidazeylanoides) Candida albicans (C.albicans) (C.albicans)Candida albicans) Candida tropicalis (A), (B)Candidatropicalis) Candida glabrata (A. glabrata)Candida glabrata) Candida parapsilosis (C.parapsilosis) (C.parapsilosis)Candidaparapsilosis) Candida Krusei (C.)Candida krusei) Candida Vicina (C.Virginiana) ((C.Virginiana))Candidalusitaniae) Candida Krusei (C.)Candida kefyr) Candida Gastriae (C.Gastri) (C.Gastri)Candidaguilliermondii) And Candida dolichiana (C.), (Candida dubliniensis). The candida species that can be treated in the compositions of the present invention are preferably candida albicans.
Pharmaceutically acceptable salts
Terbinafine or berberine of the invention may be formulated in the form of a pharmaceutically acceptable salt. Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono-, di-, tri-, tetra-, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts may facilitate pharmacological applications by altering the physical properties of the compounds without preventing them from exerting their physiological effects. Useful changes in physical properties include lowering the melting point for transungual administration, and increasing solubility for administration of higher concentrations of drug.
Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, mesylate, esylate, benzenesulfonate, p-toluenesulfonate, cyclamate, and quinic acid salts. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, fumaric acid, and quinic acid.
Pharmaceutically acceptable salts also include base addition salts when acidic functional groups such as carboxylic acids or phenols are present, such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, tert-butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc. Such salts can be prepared using the appropriate corresponding bases.
Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the compound in free base form is dissolved in a suitable solvent, such as an aqueous or aqueous-alcoholic solution containing a suitable acid, and the solution is evaporated for isolation. In another example, salts are prepared by reacting the free base and the acid in an organic solvent.
Thus, for example, if a particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, e.g., by treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, α -hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
Likewise, if a particular compound is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids (e.g., L-glycine, L-lysine, and L-arginine), ammonia, primary, secondary, and tertiary amines, and cyclic amines (e.g., hydroxyethylpyrrolidine, piperidine, morpholine, and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
Pharmaceutically acceptable salts of the compounds may exist as complexes. Examples of the complex include 8-chlorophylline complex (analogous to, for example, theohydramine: diphenhydramine 8-chlorophylline (1:1) complex; haloainin) and various cyclodextrin-containing complexes.
Example 1 synergistic antifungal Effect of terbinafine hydrochloride and Berberine hydrochloride
The advantage of the combination of terbinafine hydrochloride and berberine hydrochloride in vitro antibiosis is illustrated by respectively determining the MIC of the terbinafine hydrochloride and the berberine hydrochloride and comparing and judging the MIC value of the combination of the terbinafine hydrochloride and the berberine hydrochloride. The study was conducted with reference to protocols established by the national Clinical Laboratory Standards Institute (CLSI) and the literature relevant thereto.
The experimental method comprises the following steps: (1) configuration of drug concentration: terbinafine hydrochloride TBH and berberine hydrochloride BRH are respectively prepared into mother liquor with the concentrations of 50000 mu g/mL and 10000 mu g/mL by dimethyl sulfoxide, then the mother liquor is respectively diluted by 100 times and 20 times by RPMI1640 liquid culture medium to obtain the maximum liquid medicine concentrations of 500 mu g/mL, and then the mother liquor is diluted by RPMI1640 liquid culture medium to obtain 20 concentrations with the final concentration range of 0.0001-500 mu g/mL. (2) Preparing strains: reading the suspension of Trichophyton rubrum, Microsporum canis, Fusarium, Aspergillus fumigatus and Candida albicans with turbidimeter, and adjusting the concentration of the suspension to (1-5). times.10 with 0.85% physiological saline6CFU/mL is ready for use. In the experiment, the bacterial suspension is diluted by 10 times by 0.85% normal saline, and then is inoculated, and the final concentration is (1-5) multiplied by 105CFU/mL. (3) Determination of MIC of drug: taking 100 μ L antifungal drug terbinafine hydrochloride and berberine hydrochloride dilution with multiple ratio by using a pipette gun, sequentially adding into 1-10 column holes of each row of 96-well plate, and adding 100 μ L final concentration bacterial suspension. Column 11 is a negative control, to which 200. mu.L of RPMI1640 liquid medium was added. Column 12 is positive control, added separately100 mu L of bacterial suspension and 100 mu L of liquid culture medium, and culturing at constant temperature of 28 ℃. The results of Candida albicans, Aspergillus fumigatus and Fusarium were determined after days 2, 3 and 3 respectively, and Trichophyton rubrum and Microsporum canis were determined after day 6, and corresponding MIC values were read. All experiments were repeated 3 times. (3) Chessboard microdilution method: adopting a chessboard microdilution method, adding the medicines into a 96-well plate by using a microdispensing gun, wherein in dermatophytes (trichophyton rubrum and microsporum canis), the 1 st to 10 th rows (holes) are sequentially added into the 2 nd to 11 th rows of the 96-well plate from high concentration to low concentration (500-0.0001 mu g/mL) by taking 50 mu L of terbinafine hydrochloride diluted in multiple proportion; sequentially adding 50 muL-fold diluted berberine hydrochloride liquid medicine into lines B-H of a 96-well plate from low concentration to high concentration (0.0001-500 mug/mL), and then adding 100 muL of the bacterial suspension with final concentration; sequentially adding 50 mu L of terbinafine hydrochloride diluted in multiple times to the 2 nd to 11 th columns of a 96-well plate from high concentration to low concentration (500-0.97 mu g/mL) in non-dermatophytes (candida albicans, aspergillus fumigatus and fusarium); taking 50 muL of berberine hydrochloride liquid medicine diluted by times from low concentration to high concentration (0.97-500 mug/mL), sequentially adding into lines B-H of a 96-well plate, and then adding 100 muL of bacterial suspension with final concentration. Adding 100 μ L of RPMI1640 liquid culture medium and 100 μ L of bacterial suspension at final concentration into column 11; 200. mu.L of the medium was added to each column 12. Culturing at 28 deg.C, determining the results of the five bacteria (Trichophyton rubrum, Microsporum canis, Fusarium, Aspergillus fumigatus and Candida albicans) after 6, 3 and 2 days, reading out corresponding MIC value, and calculating antibacterial combination index (FICI). All experiments were repeated 3 times. FICI is the sum of two drugs FIC (FIC = MIC)Combination of first and second herbs/MICUsed singly for Jia Yao+ MICCombination of drugs B/MICUsed singly for treating B). The first medicine is terbinafine hydrochloride, and the second medicine is berberine hydrochloride. When the two medicines are combined for use, the evaluation mode is as follows: when the FICI is less than or equal to 0.5, the combined antibacterial effect of the two medicines is a synergistic effect; when the FICI is more than 0.5 and less than or equal to 1, the combined antibacterial effect of the two medicines is additive effect; when the FICI is more than 1 and less than or equal to 2, the combined antibacterial effect of the two medicines is irrelevant; when FICI is greater than 2, the interaction of the two drugs is antagonistic.
Table 1. MIC and FICI of terbinafine hydrochloride and berberine hydrochloride against dermatophytes and non-dermatophytes (n =3).
| MIC（μg/ml） | MICTBH-for single use | MICTBH-combination | MICBRH-single use | MICBRH-combined use | FICI | Determination |
| Trichophyton rubrum | 0.125 | 0.031 | 125.000 | 4.000 | 0.281 | Collaboration |
| Microsporum canis | 0.125 | 0.008 | 62.500 | 7.813 | 0.188 | Collaboration |
| Fusarium | 4.000 | 0.500 | 15.625 | 0.500 | 0.281 | Collaboration |
| Aspergillus fumigatus | 8.000 | 0.500 | 31.25 | 31.25 | 1.625 | Is irrelevant |
| Candida albicans | 15.625 | 1.000 | 7.813 | 1.000 | 0.188 | Collaboration |
The experimental results are as follows: the results of the chessboard microdilution method are shown in Table 1, and it can be seen that terbinafine hydrochloride and berberine hydrochloride have certain inhibitory effects (as shown by MIC values) on dermatophytes (trichophyton rubrum and microsporum canis) and non-dermatophytes (fusarium, aspergillus fumigatus and Candida albicans). In addition, when terbinafine hydrochloride and berberine hydrochloride are jointly applied for antibiosis, the MIC of the two medicines in combination is far lower than that of the single medicine, and the results of FICI values judge that the two medicines in combination show obvious effect on four kinds of bacteria such as trichophyton rubrum, microsporum canis, fusarium and candida albicansThe obvious synergistic effect proves that the two medicines are combined to have the effects of enhancing the sterilization effect, reducing the medicine dosage and shortening the treatment course, and simultaneously, because of MICCombined useValue to average ratio MICFor single useThe value is obviously reduced, and the method has good effect on avoiding drug resistance of the drug.
EXAMPLE 2 film coating agent for treating fungal nail infection disease
(1) The single-medicine composition (containing urea) of the embodiment comprises the following raw materials in percentage by mass:
terbinafine hydrochloride 1%
Eudragit®RLPO 20%
Ethanol 55 percent
10 percent of urea
14 percent of water
The preparation method of the composition of the embodiment comprises the following steps:
A. according to the formula ratio, at room temperature, terbinafine hydrochloride and ethanol are mixed to form a transparent and clear solution;
B. adding RLPO into the solution A according to the formula ratio;
C. according to the formula ratio, mixing urea and water at room temperature, carrying out ultrasonic treatment at 25 ℃ until a uniform and clear urea solution is formed, and adding the solution into the solution in the step B to obtain a solution C;
D. and continuously stirring the solution C until the RLPO is dissolved to form uniform, stable, transparent and clear liquid, thus obtaining the composite material.
(2) The combined composition (containing urea) of this example comprises the following raw materials in mass percent:
terbinafine hydrochloride 0.5%
0.5 percent of berberine hydrochloride
Eudragit®RLPO 20%
Ethanol 55 percent
10 percent of urea
14 percent of water
The preparation method of the composition of the embodiment comprises the following steps:
A. according to the formula ratio, at room temperature, terbinafine hydrochloride and ethanol are mixed to form a transparent and clear solution;
B. adding RLPO into the solution A according to the formula ratio until the RLPO is dissolved to form uniform, stable, transparent and clear liquid, and obtaining solution B;
C. according to the formula ratio, mixing urea and water at room temperature to form a uniform and clear urea solution;
D. adding berberine hydrochloride into the solution C according to the formula ratio to obtain a solution D;
E. and continuously stirring the solution D to form a uniform and stable solution, thus obtaining the compound.
(3) The single-medicine composition (without urea) of the embodiment comprises the following raw materials in percentage by mass:
terbinafine hydrochloride 1%
Eudragit®RLPO 20%
Ethanol 55 percent
24 percent of water
The preparation method of the composition of the embodiment comprises the following steps:
A. according to the formula ratio, at room temperature, terbinafine hydrochloride and ethanol are mixed to form a transparent and clear solution;
B. adding RLPO into the solution A according to the formula ratio;
C. adding water into the solution obtained in the step B at room temperature according to the formula ratio to obtain a solution C;
D. and continuously stirring the solution C until the RLPO is dissolved to form uniform, stable, transparent and clear liquid, thus obtaining the composite material.
(4) The inorganic composition (containing urea) of the embodiment comprises the following raw materials in percentage by mass:
Eudragit®RLPO 20%
ethanol 55 percent
10 percent of urea
15 percent of water
The preparation method of the composition of the embodiment comprises the following steps:
A. mixing RLPO and ethanol at room temperature according to the formula ratio;
B. according to the formula ratio, mixing urea and water at room temperature to form a uniform and clear urea solution, and adding the urea solution into the solution A to obtain a solution B;
C. and continuously stirring the solution B to form uniform, stable, transparent and clear liquid, thus obtaining the compound.
(5) The single-medicine composition (without urea; TBH 100) of the embodiment comprises the following raw materials in percentage by mass:
terbinafine hydrochloride 1%
Eudragit®RLPO 20%
Ethanol 55 percent
24 percent of water
The preparation method of the composition of the embodiment comprises the following steps:
A. according to the formula ratio, at room temperature, terbinafine hydrochloride and ethanol are mixed to form a transparent and clear solution;
B. adding RLPO into the solution A according to the formula ratio;
C. adding water into the solution obtained in the step B according to the formula ratio to obtain a solution C;
D. and continuously stirring the solution C until the RLPO is dissolved to form uniform, stable, transparent and clear liquid, thus obtaining the composite material.
EXAMPLE 4 evaluation of plastics for the treatment of fungal nail infections
One, film forming (drying time and appearance score) test
The combined composition (containing urea), the single medicine composition (containing no urea) and the commercial preparation (Lamisil Pedisan) for treating fungal nail infection disease prepared in the way®once) were examined in film forming experiments.
And (3) testing the sample: 0.2ml of the combination composition of the invention (containing urea); terbinafine hydrochloride: 0.5%, berberine hydrochloride: 0.5 percent, and the character is clear transparent liquid; 0.2ml of a single pharmaceutical composition of the invention (containing urea); terbinafine hydrochloride: 1% and is a clear transparent liquid; comparison products: 0.2ml of the composition (without urea), terbinafine hydrochloride: 1% and is a clear transparent liquid; 0.2ml of a commercial formulation (Lamisil Pedisan)®once), terbinafine hydrochloride: 1% and the character is clear and transparent semi-solid.
Experimental method of film formation time: taking 0.2ml of the combination composition (containing urea), the single-drug composition (containing urea), the composition (containing no urea) and the commercial preparation (Lamisil Pedisan) of the invention®once), the film was formed on a 2 × 2 cm square glass plate with a brush at room temperature. The time to complete the film was recorded with a stopwatch and repeated three times. Appearance scoring experimental method: taking 0.2ml of the combined composition of the invention (containing urea), the single-drug composition (containing no urea) and the commercial preparation (Lamisil Pedisan)®once), brush coated onto a 2 x 2 cm square glass plate, and the solvent evaporated to form an almost transparent film in situ. Visual scoring was performed to evaluate the appearance of the film. The combination composition (containing urea) and the single-component composition (containing urea) of the invention should have good spreadability (4 points), and have a transparent surface (4 points), smooth surface (4 points) and no precipitation (4 points). The higher the score, the better the film appearance.
The experimental results are as follows: the results of the film-forming experiments are shown in fig. 1, from which it can be seen that the combination composition (containing urea) and the single-drug composition (containing urea) according to the present invention significantly shorten the film-forming drying time, have good spreadability, and have a neat, smooth and transparent appearance, which can improve patient compliance.
Second, nail penetration test
The combined composition (containing urea) and the single-component composition (containing urea) for treating fungal nail infection disease prepared in the above way are mixed with the composition (containing no urea) and a commercial preparation (Lamisil Pedisan)®once) for nail penetration test comparison. (comparison of two experiments conducted before and after)
Experimental materials:
experiment 1
And (3) testing the sample: 0.3g of composition (containing urea), terbinafine hydrochloride: 1% and the character is clear transparent liquid.
Comparison products: 0.3g of composition (without urea), terbinafine hydrochloride: 1% and is a clear transparent liquid; 0.3g of a commercial formulation (Lamisil Pedisan)®once), terbinafine hydrochloride: 1% and the character is clear and transparent semi-solid.
Experiment 2
And (3) testing the sample: 0.3g of the combination composition (containing urea), terbinafine hydrochloride: 0.5%, berberine hydrochloride: 0.5 percent, and the character is clear and transparent yellow liquid. Comparison products: 0.3g of the single drug composition (containing urea), terbinafine hydrochloride: 0.5 percent, and the characters are clear and transparent liquid.
The experimental method comprises the following steps:
obtaining the nail: in nail penetration studies, cow hoof nails were used to replace human nails. Bovine hooves were obtained from a local slaughterhouse, and the bovine hooves were stripped of adherent cartilage and connective tissue, leaving only the bovine nail parts, and were subjected to impurity cleaning and preservation in 70% ethanol (v/v) for 24 hours. The nails were then air dried and frozen at-20 ℃ for use. To ensure uniform nail thickness for the different prescriptions, the nail was trimmed with a scalpel and sandpaper prior to testing and controlled to a thickness of about 200 microns, and visual inspection confirmed that only nail samples without any breakage could be tested. Wherein the thickness of the fingernail is measured with a vernier caliper.
A nail penetration experiment: isolated penetration test of nail. The nail of the ox is put on the nail before useThen unfreezing, washing with normal saline, and sucking the surface water by filter paper. The integrity of the nail is checked before the experiment to ensure no damage. In vitro nail penetration test, a modified Franz diffusion cell was used to hold the clipped intact nail between a supply cell and a receiving cell, the effective nail penetration area of the diffusion cell was 0.6359 cm2The volume of the receiving pool is 7.5 mL, the temperature of the water bath of the diffusion instrument is adjusted to be 32 +/-2 ℃, and the rotating speed of the stirrer is 250 rpm. In experiment 1, a single-drug composition (containing urea), a single-drug composition (containing no urea) and a commercially available preparation (Lamisil Pedisan) of the present invention containing terbinafine hydrochloride 3 mg were administered to the supply tank respectively®once), the receiving solution was pure water, and 1 mL of the receiving solution was taken 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 hours, and a blank receiving solution of the same volume was added. In experiment 2, a single-medicine composition (containing urea) and a combined composition (containing no urea) containing terbinafine hydrochloride of 1.5mg are respectively administered into a supply tank; the receiving solution is 10% hydroxypropyl-beta cyclodextrin normal saline solution (the receiving solution is different because the screening is carried out under the condition of leakage groove of berberine hydrochloride), 1 mL of receiving solution is taken for 1, 2, 4, 6, 8, 12, 24, 36, 48, 60 and 72h, and the same volume of blank receiving solution is supplemented. After the samples are filtered by a 0.22 mu m nano-pore filter membrane, the content of terbinafine hydrochloride and berberine hydrochloride in the samples is determined by high performance liquid chromatography, and the cumulative permeation quantity is calculated according to the following formula:
where Cn denotes the concentration measured at the nth sampling point, Ci denotes the concentration measured at the ith sampling point, and i =1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72 h. V denotes the volume of the receiving tank, ViThe volume of each sample is indicated and a represents the effective nail penetration area. Qn (μ g cm)2) For cumulative permeation, linear regression is performed by Q against time t, and the slope of the obtained line is the steady state permeation rate constant Js (mu g cm)-2·h-1). After the expiration of 72h of the transungual test, the fingernails were removed from the diffusion cell, demolded, and the nail surfaces were washed 3 times with water to remove residual drug, and the nails were treatedShearing, adding 2mL of methanol, performing ultrasonic treatment for 2 hours, centrifuging at 3000 rpm for 5 min, collecting supernatant, filtering with 0.22 μm microporous membrane, collecting filtrate, and measuring terbinafine hydrochloride content by high performance liquid chromatography to obtain isolated nail retention.
TABLE 2 Single drug combination of the invention (with urea), Single drug combination (without urea) and commercial formulation (Lamisil Pedisan)®once) of TBH nail penetration results
Note: *:P< 0.05, with a commercial formulation (Lamisil Pedisan)®once) comparison;+：P< 0.05, compared to a single drug composition (without urea). TBH was administered in an amount of 3 mg for each of the three formulations.
TABLE 3 TBH nail penetration results for the combination composition of the invention (with urea) and the single-drug composition (with urea)
Note: TBH was administered in an amount of 1.5mg in both formulations.
TABLE 4 BRH nail penetration results for the combination composition of the invention (containing urea)
The experimental results are as follows: the results of nail penetration are shown in tables 2, 3 and 4, from which it can be seen that the addition of urea to the single-drug composition (containing urea) of the present invention significantly increases and enhances the nail penetration and nail retention of terbinafine hydrochloride, and is compatible with the commercial formulation (Lamisil Pedisan)®once) all had statistical differences. In addition, the combined composition (containing urea) has the same penetrating effect with the single medicine composition (containing urea), which shows that the berberine hydrochloride in the composition has no penetrating and retaining effects on the single medicine composition (containing urea)The influence shows consistent transmural behavior, and meanwhile, berberine hydrochloride also shows certain transmural characteristics in a combined composition (containing urea) so as to further illustrate that the combination of the two medicines possibly has the advantage of simultaneously enhancing the antibacterial effect.
Thirdly, the research of the antifungal activity in vitro is used for evaluating the treatment effect of the product of the invention
The antifungal activity of the combination composition of the present invention (containing urea), the single drug composition (containing no urea), the non-drug composition (containing urea), the DMSO solution containing terbinafine hydrochloride (DMSO being able to dissolve the drug and having no effect on the antibacterial activity) was compared with the antifungal activity of the commercial formulation. (comparison of two experiments conducted before and after)
Experimental Material
Experiment 1
Strain: dermatophytes (trichophyton rubrum, microsporum canis) and non-dermatophytes (fusarium, aspergillus fumigatus, and candida albicans) were tested: 10 μ L (equivalent to a drug content of 100 μ g) of the single pharmaceutical composition of the invention (containing urea), terbinafine hydrochloride: 1% and the character is clear transparent liquid. Comparison products: 10 μ L of a pharmaceutical-free composition (without urea) in the form of a clear and transparent liquid; 10 μ L of a non-medicinal composition (containing urea) in the form of a clear and transparent liquid; 10 μ L (equivalent to 100 μ g of drug content) of a single drug composition (without urea), terbinafine hydrochloride: 1% and is a clear transparent liquid; 10 μ L (equivalent drug content 100 μ g) of terbinafine hydrochloride in DMSO, terbinafine hydrochloride concentration: 1% and the character is a clear solution; a commercial formulation (Lamisil Pedisan) of about 0.010 g (equivalent to a drug content of 100. mu.g) was precisely weighed®once®) Terbinafine hydrochloride: 1% and the character is clear and transparent semi-solid.
Experiment 2
(1) Strain: dermatophytes (trichophyton rubrum, microsporum canis) test article: 5 μ L (equivalent to 25 μ g of TBH-containing dose) of the combination composition of the invention (containing urea), terbinafine hydrochloride: 0.5 percent; 0.5 percent of berberine hydrochloride; the character is clear and transparent yellow liquid. (because terbinafine hydrochloride herein has effects on skin tineaThe bacteria inhibiting effect is more obvious, so the dosage is reduced to conveniently compare the antibacterial effect of different groups) of reference substances: 5 μ L (equivalent to 25 μ g) of the single pharmaceutical composition of the invention (containing urea), terbinafine hydrochloride: 0.5 percent, and the character is clear transparent liquid; a commercial formulation (Lamisil Pedisan) weighing precisely about 0.0025 g (equivalent to 25. mu.g drug content)®) Terbinafine hydrochloride: 1% and the character is clear and transparent semi-solid. (since terbinafine hydrochloride has a significant inhibitory effect on dermatophytes, the dosage is reduced to facilitate comparison of antibacterial effects of different groups)
(2) Strain: non-dermatophytes (Candida albicans, Aspergillus fumigatus, Fusarium)
And (3) testing the sample: 20 μ L (equivalent to 100 μ g of TBH) of the combination composition of the invention (containing urea), terbinafine hydrochloride: 0.5 percent; 0.5 percent of berberine hydrochloride; the character is clear and transparent bright yellow liquid. (since terbinafine hydrochloride had a weak inhibitory effect on non-dermatophytes, the dose was consistent with that of experiment 1): 20 μ l (equivalent to a drug content of 100 μ g) of the single pharmaceutical composition of the invention (containing urea), terbinafine hydrochloride: 0.5 percent, and the character is clear transparent liquid; commercial formulation (Lamisil Pedisan)®) Terbinafine hydrochloride: 1% and the character is clear and transparent semi-solid. (since terbinafine hydrochloride had a weak inhibitory effect on non-dermatophytes, the dose was the same as that in experiment 1)
Antifungal test methods:
(1) activation of strains (trichophyton rubrum, microsporum canis, fusarium, aspergillus fumigatus and candida albicans): inoculating and picking strains in an SDA culture medium, scratching, performing inverted culture overnight (28 +/-2 ℃), culturing trichophyton rubrum and microsporum canis for 6 days, and performing upright culture and observation; the fusarium, aspergillus and candida albicans are right-standing the next day, and culturing and observing.
(2) Preparing bacterial liquid: selecting activated single colony, adding 0.85% physiological saline 2ml, mixing, collecting upper layer homogeneous solution, and adjusting to 0.5 McLett unit ((1-5) × 10) with turbidimeter6CFU/ml）。
(3) Drug sensitivity test: and (3) dipping the sterile cotton swab with the bacterial suspension, uniformly coating the bacterial suspension on the surface of an RPMI-1640 agar culture medium along 3 directions, placing 1-2 paper sheets on each dish after drying, dropwise adding the test product and the reference product with the corresponding contents, repeating each composition for 3 times, and further observing and culturing after each prescription forms a film.
(4) The trichophyton rubrum and microsporum canis are grown and cultured at 28 +/-2 ℃, and are observed after the 6 th day, and the size of the inhibition zone is measured by a vernier scale.
(5) Fusarium, Aspergillus fumigatus and Candida albicans were grown and cultured at 35 + -2 deg.C, observed after 2, 3 and 3 days, respectively, and the size of the zone of inhibition was measured by a vernier caliper.
TABLE 5 inhibition zone size (unit: mm) for dermatophytes and non-dermatophytes for different compositions respectively
| Prescription | Trichophyton rubrum | Microsporum canis | Fusarium | Aspergillus fumigatus | Candida albicans |
| Liquid medicine (DMSO solution) | 80.00±0.00 | 77.00±0.00* | 31.00±0.58* | 27.67±0.58* | 15.00±1.00* |
| Commercial formulation (Lamisil Pedisan;. TBH 100) | 80.00±0.00 | 68.20±0.01# | 27.00±1.00# | 15.33±0.58# | 10.00±0.00*,# |
| Pharmaceutical composition (without urea) | 10.00±0.00*,# | 10.00±0.00*,# | 10.00±0.00*,# | 10.00±0.00*,# | 10.00±0.00*,# |
| Inorganic medicine composition (containing urea) | 10.00±0.00C,# | 10.00±0.00*,# | 10.00±0.00*,# | 10.00±0.00*,# | 10.00±0.00*,# |
| Single drug composition (without urea; TBH 100) | 80.00±0.00 | 75.50±0.67* | 31.67±0.58* | 23.67±0.58* | 10.00±0.00*,# |
| Single medicine composition (containing urea; TBH 100) | 80.00±0.00 | 77.25±0.58* | 31.33±0.58* | 26.33±1.52* | 10.00±0.00*,# |
*：P< 0.05, with a commercial formulation (Lamisil Pedisan)®）；#：P< 0.05, liquid medicine (DMSO solution).
TABLE 6 inhibition zone size (unit: mm) for dermatophytes for different compositions respectively
| Prescription | Trichophyton rubrum | Microsporum canis |
| Combined composition (containing urea; TBH 25) | 59.67±0.58*,+ | 73.00±0.58*,+ |
| Single medicine composition (containing urea; TBH 25) | 51.33±0.58* | 67.00±1.00* |
| Commercial formulation (Lamisil Pedis)an ®;TBH25） | 47.00±1.00+ | 56.00±1.00+ |
*: p < 0.05, with a commercial formulation (Lamisil Pedisan)®) (ii) a +: p is less than 0.05, and the single-medicine composition (containing urea).
TABLE 7 inhibition zone size (unit: mm) for various compositions for non-dermatophytes, respectively
| Prescription | Fusarium | Aspergillus fumigatus | Candida albicans |
| Combined composition (containing urea; TBH 100) | 24.67±0.58*,+ | 17.00±1.00*,+ | 17.00±1.00*,+ |
| Single medicine composition (containing urea; TBH 100) | 20.33±0.58* | 12.67±0.61* | 10.00±0.00* |
| Commercial formulation (Lamisil Pedisan;. TBH 100) | 13.00±0.58+ | 10.00±0.03+ | 10.00±0.00+ |
The experimental results are as follows: the results of the antifungal experiments from tables 5, 6 and 7 above show that:
(1) in bacteriostatic experiments of dermatophytes (trichophyton rubrum and microsporum canis):
① in Table 5 results of experiment 1, in resisting Trichophyton rubrum, single drug composition (containing urea), single drug composition (containing no urea), drug solution (DMSO solution) and commercial preparation (Lamisil Pedisan)®once) are consistent, the antibacterial effect is completely inhibited under the dosage (TBH dosage is 100 mug), the inhibition zones are all larger than 80 mm (the diameter of the whole culture dish is equal to 80 mm), which is probably related to the stronger antibacterial effect of terbinafine hydrochloride on trichophyton rubrum; in the anti-microsporidia canis, the single-medicine composition (containing urea) and the liquid medicine (DMSO solution) have consistent antibacterial effect, show stronger antibacterial effect and are superior to the commercial preparation (Lamisil Pedisan)®once) and had significant statistical differences. In addition, the zone of inhibition (77.25 mm) was found to be greater for the single drug combination (urea-containing) than for the single drug combination (urea-free) (75.50 mm). Meanwhile, the addition of urea is proved to further solubilize TBH in a culture medium in a water environment so as to increase the release of the drug and enhance the drug effect.
② in the results of Table 6 and Table 7 of experiment 2, because terbinafine hydrochloride has strong correlation with the antibacterial effect on dermatophytes and the antibacterial cycle is too large to judge the antibacterial advantage of the combination of the two medicines, the dosage of each composition (TBH content is 25 mug) is reduced respectively, the results of each composition are compared conveniently, and the results show that the antibacterial effect of the combination composition (containing urea) and the single medicine composition (containing urea) on both trichophyton rubrum and microsporum canis is obviously better than that of the commercial preparation (Lamisil Pedisan)®once); combined with the antibacterial effect of the composition (containing urea)The effect is obviously superior to that of a single-medicine composition (containing urea), which shows that the addition of the berberine hydrochloride is beneficial to improving the antibacterial effect of the single-medicine terbinafine hydrochloride, and the combination of the terbinafine hydrochloride and the berberine hydrochloride has synergistic effect and is consistent with the chessboard microdilution method result.
(2) Bacteriostasis test of non-dermatophytes (fusarium, aspergillus fumigatus and candida albicans)
① in Table 5 of experiment 1, the single drug composition (containing urea) and the drug solution (DMSO solution) have equivalent antibacterial effects on fusarium and aspergillus fumigatus at the dosage (TBH content of 100 μ g), and both have stronger antibacterial effects, which are significantly better than those of the commercial preparation (Lamisil Pedisan)®once); compared with the single-medicine composition (containing urea), the single-medicine composition (containing urea) has larger bacteriostasis effect (the bacteriostasis zone of the former is 26.33 mm, and the bacteriostasis zone of the latter is 23.67 mm) in resisting aspergillus fumigatus, which shows that the solubilization effect of urea can help the further release of the medicine to improve the efficacy; in addition, in the anti-candida albicans experiment, at the administration amount (TBH content of 100 mug), a single-drug composition (containing urea), a single-drug composition (containing no urea) and a commercial preparation (Lamisil Pedisan) showed a certain bacteriostatic effect on candida albicans except for that a drug solution (DMSO solution, which does not have the problem of drug release)®once) has no antibacterial effect on candida albicans, which is related to the poor inhibition effect of terbinafine hydrochloride on candida albicans and the drug diffusion.
② in the results of Table 6 and Table 7 of experiment 2, it was shown that the combination composition (containing urea) and the single-drug composition (containing urea) had a higher antibacterial effect against Fusarium and Aspergillus fumigatus than the commercial formulation (Lamisil Pedisan)®once) is also more remarkable, wherein the antibacterial effect of the combined composition (containing urea) is remarkably superior to that of the single-medicine composition (containing urea), and the combined composition has a remarkable enhancing effect; in addition, in the experiments of resisting Candida albicans, the combined composition (containing urea) with the inhibition zone of 17.00mm shows a remarkable antibacterial effect, and compared with the single medicine composition (containing urea) and a commercial preparation (Lamisil Pedisan) (with the inhibition zone of 10.00 mm), the combined composition has remarkable improvement on the antibacterial effectHigh, showing great advantages. The addition of the berberine hydrochloride is helpful to improve the antibacterial effect of the single-drug terbinafine hydrochloride on non-dermatophytes, and shows obvious enhancing effect.
In conclusion, the combined composition (containing urea) showed significant antibacterial activity against both dermatophytes such as trichophyton rubrum and microsporum canis, and non-dermatophytes such as fusarium, aspergillus fumigatus and candida albicans in antifungal experiments. Wherein, the addition of the urea further improves the drug effect by solubilizing the drug; meanwhile, the combined use of the berberine hydrochloride also greatly improves the antibacterial effect of the single-drug terbinafine hydrochloride, shows the synergistic interaction with the terbinafine, and effectively widens the antibacterial spectrum of the single-drug terbinafine hydrochloride so as to achieve the effective treatment of fungal infection of the nail.
Claims (10)
1. An antifungal composition comprising:
a) terbinafine or a pharmaceutically acceptable salt thereof;
b) berberine or a pharmaceutically acceptable salt thereof; and
c) urea.
2. The composition according to claim 1, wherein the composition further comprises a film forming material and the composition is a film coating, wherein the film forming material is preferably polyvinyl alcohol, polyvinyl pyrrolidone, carbomer, chitosan or Eudragit RLPO.
3. The composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of terbinafine is the hydrochloride salt.
4. The composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of berberine is hydrochloride.
5. Use of any one of the compositions of claims 1-4 in the manufacture of a medicament for treating a fungal infection disease, wherein the fungus is selected from the group consisting of trichophyton, fusarium, candida, and combinations thereof.
6. Use of a pharmaceutical composition for the manufacture of a medicament for the treatment of a fungal infection disease, said pharmaceutical composition comprising:
terbinafine or a pharmaceutically acceptable salt thereof, and
berberine or a pharmaceutically acceptable salt thereof; wherein the content of the first and second substances,
the fungus is selected from the group consisting of trichophyton, fusarium, candida and combinations thereof.
7. Use according to claim 5 or 6, wherein the fungus is selected from the group consisting of Trichophyton rubrum, Fusarium, Candida albicans and combinations thereof.
8. The use according to claim 5 or 6, wherein the fungal infection disease is onychomycosis.
9. The use according to claim 7, wherein the pharmaceutically acceptable salt of terbinafine is the hydrochloride salt.
10. The use according to claim 7, wherein the pharmaceutically acceptable salt of berberine is hydrochloride.
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